WO1998031657A1 - PREPARATION D'AMIDES DE L'ACIDE α-AMINO-CARBOXYLIQUE - Google Patents

PREPARATION D'AMIDES DE L'ACIDE α-AMINO-CARBOXYLIQUE Download PDF

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Publication number
WO1998031657A1
WO1998031657A1 PCT/US1997/024066 US9724066W WO9831657A1 WO 1998031657 A1 WO1998031657 A1 WO 1998031657A1 US 9724066 W US9724066 W US 9724066W WO 9831657 A1 WO9831657 A1 WO 9831657A1
Authority
WO
WIPO (PCT)
Prior art keywords
amide
carboxylic acid
amino carboxylic
amino
acid amide
Prior art date
Application number
PCT/US1997/024066
Other languages
English (en)
Inventor
Roger R. Gaudette
John B. Stallman
Original Assignee
Hampshire Chemical Corp.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hampshire Chemical Corp. filed Critical Hampshire Chemical Corp.
Priority to AU57239/98A priority Critical patent/AU728197B2/en
Priority to BR9714185-2A priority patent/BR9714185A/pt
Priority to EP97953506A priority patent/EP0964848A4/fr
Priority to JP53336598A priority patent/JP2001508073A/ja
Priority to DE0964848T priority patent/DE964848T1/de
Priority to CA002274527A priority patent/CA2274527A1/fr
Publication of WO1998031657A1 publication Critical patent/WO1998031657A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a process for producing ⁇ -amino carboxylic acid amides.
  • Such amides are useful as intermediates for N-substituted heterocyclic pharmaceutical compositions useful in the treatment of cardiovascular diseases including hypertension, as well as glaucoma, diabetic retinopathy and renal insufficiency.
  • the pharmaceutical compositions demonstrate antagonistic action against angiotensin II, a potent vasopressor.
  • U.S. Patent No. 5,352,788 discloses a synthesis that involves the hydrolysis of the oxalate salt of the aminonitrile using concentrated sulfuric acid, followed by treatment with ammonia and then extraction with chloroform containing 5% methanol .
  • this method has many disadvantages. It is therefore an object of the present invention to provide a method of producing aminoamides directly from the corresponding aminonitrile.
  • the problems of the prior art have been overcome by the present invention, which provides a method of preparing ⁇ -amino carboxylic acid amides directly from aminonitriles in high yield and purity by acid hydrolysis.
  • the method involves preparing the amide hydrochloride directly from the corresponding aminonitrile in the presence of water, a strong mineral acid such as HCl, and an organic solvent in which the resulting salt of the aminonitrile is insoluble or substantially insoluble.
  • HCl the hydrochloride salt readily precipitates from the solvent, and can be isolated by filtration in high purity. The solvent and excess HCl can be recycled with no significant color build-up or product quality deterioration.
  • the present invention can be .used in connection with any ⁇ -amino carboxylic acid, provided that the corresponding salt is insoluble in the solvent employed.
  • Suitable ⁇ -amino carboxylic acids include valine, glycine, alanine and leucine, with glycine, leucine and cycloleucine being particularly- preferred.
  • the amino nitrile can be virtually any ⁇ -aminonitrile corresponding to the ⁇ -amino carboxylic acid desired, and can be prepared from the corresponding ketone by conventional means well known to those skilled in the art.
  • the ketone in a suitable solvent such as methanol can be reacted with an ammonia source (such as ammonia and ammonium chloride) and a cyanide source (such as alkali metal cyanide) , and the resulting amino nitrile can be recovered by extraction with methylene chloride and dried.
  • an ammonia source such as ammonia and ammonium chloride
  • a cyanide source such as alkali metal cyanide
  • the amino nitrile is dissolved in a solvent in which the amino carboxylic acid amide salt readily precipitates.
  • suitable solvents include dialkyl ethers such as diethyl ether, and dialkyl ethylene glycols such as ethylene glycol dimethyl, diethyl, dibutyl, butyl methyl and propyl ethyl ether; secondary alcohols such as isopropanol (preferably anhydrous) ; hydrocarbons such as heptane and hexane; and ketones such as acetone.
  • the particular solvent should be chosen such that it is a solvent in which the amino nitrile has sufficient solubility to by acid hydrolyzed, and in which the salt formed by the reaction is at least substantially insoluble, ensuring that it can be easily isolated from the reaction medium. As the solubility of the salt in the solvent increases, the yield will decrease. Ether solvents are preferred, with dimethoxyethane being an especially preferred solvent.
  • Water is added to the reaction medium, preferably in an amount of about 0.5 to 4 equivalents based upon the amount of amino nitrile employed, most preferably one equivalent based upon the amount of amino nitrile employed. High excesses of water lead to the production of the amino acid rather than the desired amide.
  • the reaction mixture is then cooled to a temperature in the range of 0-50°C,. preferably below about 30°, most preferably to about 10 °C, and a suitably strong mineral acid is added while keeping the reaction temperature within the aforementioned range and preferably below about 30°C. Higher temperatures tend to result in undesirable side reactions.
  • Suitable mineral acids include HCl, HBr, H 2 S0 4 , toluene sulfonic acid, methane sulfonic acid and trifluoro acetic acid. Since excess water is deleterious to the reaction, leading to the generation of alkyl chloride, for example, it is preferred that the strong mineral acid be added in anhydrous form, especially once the appropriate amount of water is already in the system. Suitable amounts of mineral acid range from about 1 to about 6 equivalents, with 3-4 equivalents being preferred in order to reduce reaction times. Preferably the acid is added over time, such as 60 minutes.
  • the reaction mixture is sealed, warmed to a temperature of about 40°C or higher to effect conversion to the ⁇ -amino carboxylic amide salt, allowed to react to completion (about 4-20 hours), and cooled.
  • a closed system is used, since at temperatures higher than 40°C, the loss of acid gas to the atmosphere becomes problematic. At temperatures below 40°C, the reaction is very sluggish.
  • the resulting amide salt readily precipitates, which allows for easy isolation and purification.
  • the salt can be collected by filtration and washed with additional solvent.
  • amide salt can be easily converted to the free amide acid by the addition of a suitable alkaline reagent, such as ammonium hydroxide or alkali metal hydroxide, preferably sodium or potassium hydroxide .
  • a suitable alkaline reagent such as ammonium hydroxide or alkali metal hydroxide, preferably sodium or potassium hydroxide .
  • the amino nitrile of cyclopentanone was prepared using methods commonly found in the literature.
  • the amino nitrile of cyclopentanone (40.00g, 0.36 mole) was added to a 500 ml round bottom flask equipped with a mechanical ⁇ tirrer, a thermocouple, and a gas inlet tube.
  • DME dimethoxyethane
  • 6.55g (0.36 mole) of water
  • the reaction was cooled to ⁇ 10°C.
  • Anhydrous HCl (53.14g, 1.46 moles) was bubbled into the reaction mixture keeping the reaction temperature below 30°C. The HCl was added over a 60 minute period.
  • EXAMPLE 2 2.8 g (0.05 ol) of anhydrous, liquid glycinonitrile was dissolved in 1, 2-dimethoxyethane in a 125 ml Erlenmeyer flask. 9.2 g of anhydrous HCl was bubbled into the flask with cooling to the desired weight. 0.9 g (0.05 mol) of water was added, and the reaction mixture was stirred at the desired temperature for 6 hours. The product was filtered off, washed with additional solvent, and dried under vacuum. The yield of amide was 92.0%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé permettant de préparer des amides de l'acide α-amino-carboxylique directement à partir d'aminonitriles, avec des rendements et une pureté élevés, par hydrolyse acide. Selon le procédé, on prépare le sel d'amide, le chlorhydrate d'amide par exemple, directement à partir de l'aminonitrile correspondant en présence d'eau, d'un acide minéral fort tel que le HCl anhydre, et d'un solvant organique dans lequel le sel d'amide obtenu est insoluble ou sensiblement insoluble. Les solvants organiques appropriés sont les dialkyléthers, les dialkyl-éthylèneglycol-éthers et les alcools secondaires.
PCT/US1997/024066 1997-01-16 1997-12-22 PREPARATION D'AMIDES DE L'ACIDE α-AMINO-CARBOXYLIQUE WO1998031657A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU57239/98A AU728197B2 (en) 1997-01-16 1997-12-22 Preparation of alpha-amino carboxylic acid amides
BR9714185-2A BR9714185A (pt) 1997-01-16 1997-12-22 Preparação de amidas de ácido a-amino carboxìlico
EP97953506A EP0964848A4 (fr) 1997-01-16 1997-12-22 Preparation d'amides de l'acide alpha-amino-carboxylique
JP53336598A JP2001508073A (ja) 1997-01-16 1997-12-22 α−アミノカルボン酸アミドの製法
DE0964848T DE964848T1 (de) 1997-01-16 1997-12-22 Preparation of alpha-amino carboxylic acid amides
CA002274527A CA2274527A1 (fr) 1997-01-16 1997-12-22 Preparation d'amides de l'acide .alpha.-amino-carboxylique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78481897A 1997-01-16 1997-01-16
US08/784,818 1997-01-16

Publications (1)

Publication Number Publication Date
WO1998031657A1 true WO1998031657A1 (fr) 1998-07-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/024066 WO1998031657A1 (fr) 1997-01-16 1997-12-22 PREPARATION D'AMIDES DE L'ACIDE α-AMINO-CARBOXYLIQUE

Country Status (12)

Country Link
EP (1) EP0964848A4 (fr)
JP (1) JP2001508073A (fr)
KR (1) KR20000070259A (fr)
CN (1) CN1244858A (fr)
AU (1) AU728197B2 (fr)
BR (1) BR9714185A (fr)
CA (1) CA2274527A1 (fr)
DE (1) DE964848T1 (fr)
ES (1) ES2143445T1 (fr)
IN (1) IN187448B (fr)
WO (1) WO1998031657A1 (fr)
ZA (1) ZA98115B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008145626A1 (fr) * 2007-05-31 2008-12-04 Basf Se Procédé de fabrication de nitriles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950788A (en) * 1988-02-25 1990-08-21 Allied Colloids Limited Process for producing unsaturated carboxylic acids
US5606098A (en) * 1994-02-04 1997-02-25 Ao "Avtokoninvest" Amides and esters of perfluoropolyoxaalkylene-sulfo- or perfluoropolyoxaalkylene-carboxylic acids and a process for producing same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017510A (en) * 1975-11-12 1977-04-12 American Cyanamid Company Imidazoisoindolediones and the use thereof as herbicidal agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950788A (en) * 1988-02-25 1990-08-21 Allied Colloids Limited Process for producing unsaturated carboxylic acids
US5606098A (en) * 1994-02-04 1997-02-25 Ao "Avtokoninvest" Amides and esters of perfluoropolyoxaalkylene-sulfo- or perfluoropolyoxaalkylene-carboxylic acids and a process for producing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0964848A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008145626A1 (fr) * 2007-05-31 2008-12-04 Basf Se Procédé de fabrication de nitriles

Also Published As

Publication number Publication date
AU5723998A (en) 1998-08-07
ZA98115B (en) 1998-07-09
EP0964848A4 (fr) 2004-08-04
CN1244858A (zh) 2000-02-16
JP2001508073A (ja) 2001-06-19
AU728197B2 (en) 2001-01-04
DE964848T1 (de) 2001-02-08
CA2274527A1 (fr) 1998-07-23
IN187448B (fr) 2002-04-27
EP0964848A1 (fr) 1999-12-22
BR9714185A (pt) 2000-02-29
KR20000070259A (ko) 2000-11-25
ES2143445T1 (es) 2000-05-16

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